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Increased Voluntary Alcohol Consumption in Mice Lacking GABA(B(1)) Is Associated With Functional Changes in Hippocampal GABA(A) Receptors

Gamma-aminobutyric acid type B receptor (GABA(B)R) has been extensively involved in alcohol use disorders; however, the mechanisms by which this receptor modulates alcohol drinking behavior remain murky. In this study, we investigate alcohol consumption and preference in mice lacking functional GABA...

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Autores principales: Floris, Gabriele, Asuni, Gino Paolo, Talani, Giuseppe, Biggio, Francesca, Pisu, Maria Giuseppina, Zanda, Mary Tresa, Contu, Liliana, Maciocco, Elisabetta, Serra, Mariangela, Follesa, Paolo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9218813/
https://www.ncbi.nlm.nih.gov/pubmed/35755407
http://dx.doi.org/10.3389/fnbeh.2022.893835
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author Floris, Gabriele
Asuni, Gino Paolo
Talani, Giuseppe
Biggio, Francesca
Pisu, Maria Giuseppina
Zanda, Mary Tresa
Contu, Liliana
Maciocco, Elisabetta
Serra, Mariangela
Follesa, Paolo
author_facet Floris, Gabriele
Asuni, Gino Paolo
Talani, Giuseppe
Biggio, Francesca
Pisu, Maria Giuseppina
Zanda, Mary Tresa
Contu, Liliana
Maciocco, Elisabetta
Serra, Mariangela
Follesa, Paolo
author_sort Floris, Gabriele
collection PubMed
description Gamma-aminobutyric acid type B receptor (GABA(B)R) has been extensively involved in alcohol use disorders; however, the mechanisms by which this receptor modulates alcohol drinking behavior remain murky. In this study, we investigate alcohol consumption and preference in mice lacking functional GABA(B)R using the 2-bottle choice paradigm. We found that GABA(B(1)), knockout (KO), and heterozygous (HZ) mice drank higher amounts of an alcoholic solution, preferred alcohol to water, and reached higher blood alcohol concentrations (BACs) compared to wild-type (WT) littermates. The GABA(B)R agonist GHB significantly reduced alcohol consumption in the GABA(B(1)) HZ and WT but not in the KO mice. Next, because of a functional crosstalk between GABA(B)R and δ-containing GABA(A) receptor (δ-GABA(A)R), we profiled δ subunit mRNA expression levels in brain regions in which the crosstalk was characterized. We found a loss of the alcohol-sensitive GABA(A)R δ subunit in the hippocampus of the GABA(B(1)) KO alcohol-naïve mice that was associated with increased ɣ(2) subunit abundance. Electrophysiological recordings revealed that these molecular changes were associated with increased phasic inhibition, suggesting a potential gain of synaptic GABA(A)R responsiveness to alcohol that has been previously described in an animal model of excessive alcohol drinking. Interestingly, voluntary alcohol consumption did not revert the dramatic loss of hippocampal δ-GABA(A)R occurring in the GABA(B(1)) KO mice but rather exacerbated this condition. Finally, we profiled hippocampal neuroactive steroids levels following acute alcohols administration in the GABA(B(1)) KO and WT mice because of previous involvement of GABA(B)R in the regulation of cerebral levels of these compounds. We found that systemic administration of alcohol (1.5 g/kg) did not produce alcohol-induced neurosteroid response in the GABA(B(1)) KO mice but elicited an expected increase in the hippocampal level of progesterone and 3α,5α-THP in the WT controls. In conclusion, we show that genetic ablation of the GABA(B(1)) subunit results in increased alcohol consumption and preference that were associated with functional changes in hippocampal GABA(A)R, suggesting a potential mechanism by which preference for alcohol consumption is maintained in the GABA(B(1)) KO mice. In addition, we documented that GABA(B(1)) deficiency results in lack of alcohol-induced neurosteroids, and we discussed the potential implications of this finding in the context of alcohol drinking and dependence.
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spelling pubmed-92188132022-06-24 Increased Voluntary Alcohol Consumption in Mice Lacking GABA(B(1)) Is Associated With Functional Changes in Hippocampal GABA(A) Receptors Floris, Gabriele Asuni, Gino Paolo Talani, Giuseppe Biggio, Francesca Pisu, Maria Giuseppina Zanda, Mary Tresa Contu, Liliana Maciocco, Elisabetta Serra, Mariangela Follesa, Paolo Front Behav Neurosci Neuroscience Gamma-aminobutyric acid type B receptor (GABA(B)R) has been extensively involved in alcohol use disorders; however, the mechanisms by which this receptor modulates alcohol drinking behavior remain murky. In this study, we investigate alcohol consumption and preference in mice lacking functional GABA(B)R using the 2-bottle choice paradigm. We found that GABA(B(1)), knockout (KO), and heterozygous (HZ) mice drank higher amounts of an alcoholic solution, preferred alcohol to water, and reached higher blood alcohol concentrations (BACs) compared to wild-type (WT) littermates. The GABA(B)R agonist GHB significantly reduced alcohol consumption in the GABA(B(1)) HZ and WT but not in the KO mice. Next, because of a functional crosstalk between GABA(B)R and δ-containing GABA(A) receptor (δ-GABA(A)R), we profiled δ subunit mRNA expression levels in brain regions in which the crosstalk was characterized. We found a loss of the alcohol-sensitive GABA(A)R δ subunit in the hippocampus of the GABA(B(1)) KO alcohol-naïve mice that was associated with increased ɣ(2) subunit abundance. Electrophysiological recordings revealed that these molecular changes were associated with increased phasic inhibition, suggesting a potential gain of synaptic GABA(A)R responsiveness to alcohol that has been previously described in an animal model of excessive alcohol drinking. Interestingly, voluntary alcohol consumption did not revert the dramatic loss of hippocampal δ-GABA(A)R occurring in the GABA(B(1)) KO mice but rather exacerbated this condition. Finally, we profiled hippocampal neuroactive steroids levels following acute alcohols administration in the GABA(B(1)) KO and WT mice because of previous involvement of GABA(B)R in the regulation of cerebral levels of these compounds. We found that systemic administration of alcohol (1.5 g/kg) did not produce alcohol-induced neurosteroid response in the GABA(B(1)) KO mice but elicited an expected increase in the hippocampal level of progesterone and 3α,5α-THP in the WT controls. In conclusion, we show that genetic ablation of the GABA(B(1)) subunit results in increased alcohol consumption and preference that were associated with functional changes in hippocampal GABA(A)R, suggesting a potential mechanism by which preference for alcohol consumption is maintained in the GABA(B(1)) KO mice. In addition, we documented that GABA(B(1)) deficiency results in lack of alcohol-induced neurosteroids, and we discussed the potential implications of this finding in the context of alcohol drinking and dependence. Frontiers Media S.A. 2022-06-09 /pmc/articles/PMC9218813/ /pubmed/35755407 http://dx.doi.org/10.3389/fnbeh.2022.893835 Text en Copyright © 2022 Floris, Asuni, Talani, Biggio, Pisu, Zanda, Contu, Maciocco, Serra and Follesa. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Neuroscience
Floris, Gabriele
Asuni, Gino Paolo
Talani, Giuseppe
Biggio, Francesca
Pisu, Maria Giuseppina
Zanda, Mary Tresa
Contu, Liliana
Maciocco, Elisabetta
Serra, Mariangela
Follesa, Paolo
Increased Voluntary Alcohol Consumption in Mice Lacking GABA(B(1)) Is Associated With Functional Changes in Hippocampal GABA(A) Receptors
title Increased Voluntary Alcohol Consumption in Mice Lacking GABA(B(1)) Is Associated With Functional Changes in Hippocampal GABA(A) Receptors
title_full Increased Voluntary Alcohol Consumption in Mice Lacking GABA(B(1)) Is Associated With Functional Changes in Hippocampal GABA(A) Receptors
title_fullStr Increased Voluntary Alcohol Consumption in Mice Lacking GABA(B(1)) Is Associated With Functional Changes in Hippocampal GABA(A) Receptors
title_full_unstemmed Increased Voluntary Alcohol Consumption in Mice Lacking GABA(B(1)) Is Associated With Functional Changes in Hippocampal GABA(A) Receptors
title_short Increased Voluntary Alcohol Consumption in Mice Lacking GABA(B(1)) Is Associated With Functional Changes in Hippocampal GABA(A) Receptors
title_sort increased voluntary alcohol consumption in mice lacking gaba(b(1)) is associated with functional changes in hippocampal gaba(a) receptors
topic Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9218813/
https://www.ncbi.nlm.nih.gov/pubmed/35755407
http://dx.doi.org/10.3389/fnbeh.2022.893835
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